sta-9090 and angiogenin

Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Collagen; Colorectal Neoplasms; Down-Regulation; Drug Combinations; Female; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; HSP90 Heat-Shock Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Laminin; Mice, Nude; Platelet-Derived Growth Factor; Proteoglycans; Rectal Neoplasms; Ribonuclease, Pancreatic; RNA, Messenger; Specific Pathogen-Free Organisms; STAT3 Transcription Factor; Transforming Growth Factor beta1; Triazoles; Vascular Endothelial Growth Factor A; Vesicular Transport Proteins; Xenograft Model Antitumor Assays